DESCRIPTION (provided by investigator): Malaria remains a major health problem throughout virtually all of sub-Saharan Africa. The major manner in which this deadly disease is controlled is through control of the mosquitoes that transmit it. The work proposed here will contribute to our knowledge of ways to control malaria transmission through control of the species of Anopheles that transmit the deadliest human form of malaria, that caused by Plasmodium falciparum. The project takes an evolutionary approach to identifying genes of the innate immune system of the mosquitoes that act to kill or inhibit infection by the malaria parasite. There are four cases of Anopheles in sub-Saharan Africa having picked up P. falciparum and become major vectors to humans. We propose to study mosquito innate immune genes in all four cases. During the period of this application we can examine on the order of 25 to 30 genes in about 25 species of mosquitoes, both vectors and closely related non-vectors that act as controls. The goal is to discover what genes specifically evolve in response to falciparum infection. Once mosquito genes are identified to be implicated in specifically coevolving with falciparum infections, we will carry out a series of analytical studies to detect specific regions of the responding genes that are involved. Questions of whether the same genes and/or gene regions respond similarly in four different trials or whether in each case the evolutionary response is unique will be addressed. Identification of such genes can lead to manipulation of them to produce mosquitoes incapable of transmitting falciparum while leaving the rest of the immune system intact, thus enhancing the fitness of the manipulated mosquitoes. Replacing natural vector populations with such strains require that the strain have high fitness.